Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions in the form of a clear, colorless or slightly yellowish, viscous solution.
1 ml
paclitaxel 6 mg
Excipients: macrogol glycerylriciniloleate - 527 mg, citric acid anhydrous - 2 mg, absolute ethanol - 396 mg (up to 933 mg, equivalent to 1 ml).
16.7 ml - bottles of glass, covered with a transparent film of p / e (1) - packs of cardboard.
50 ml - bottles of glass, covered with a transparent film of p / e (1) - packs of cardboard.
Set No. 2: carton pack, device elements for infusion systems and syringes for dilution and administration of "Tevadaptor" drugs (adapter to vial, syringe adapter, syringe adapter) with instructions for using the device in a cardboard box with a cardboard seal or without him and with the control of the first autopsy.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Antitumor drug of plant origin. Paclitaxel is obtained semi-synthetically from the plant Taxus Baccata.
The mechanism of action is associated with the ability to stimulate the "assembly" of microtubules from dimeric tubulin molecules, stabilize their structure and inhibit dynamic reorganization in the interphase, which disrupts the mitotic function of the cell.
PHARMACOKINETICS
Suction
With iv introduction for 3 hours at a dose of 135 mg / m C max is 2170 ng / ml, AUC - 7952 ng / h / ml; when the same dose was administered for 24 hours, 195 ng / ml and 6300 ng / h / ml, respectively. C max and AUC are dose-dependent: with a 3-hour infusion, increasing the dose to 175 mg / m 2 leads to an increase in these parameters by 68% and 89%, and at 24-hour - by 87% and 26%, respectively.
Distribution
Binding to plasma proteins - 88-98%. The time of half-distribution from the blood in the tissue is 30 minutes. Easily penetrates and absorbs tissues, accumulates mainly in the liver, spleen, pancreas, stomach, intestines, heart, muscles.
Metabolism and excretion
It is metabolized in the liver by hydroxylation with the participation of CYP2D8 isoenzymes (with the formation of the metabolite - 6-alpha-hydroxypaclitaxel) and CYP3A4 (with the formation of metabolites 3-para-hydroxypaclitaxel and 6-alpha, 3-para-dihydroxy paclitaxel). It is excreted mainly with bile - 90%. With repeated infusions do not cumulate.
T 1/2 and total clearance are variable and depend on the dose and duration of IV administration: 13.1-52.7 h and 12.2-23.8 l / h / m 2, respectively. After intravenous infusions (1-24 hours), the total excretion of the kidneys is 1.3-12.6% of the dose (15-275 mg / m 2 ), which indicates the presence of intensive extrarenal clearance.
INDICATIONS
Ovarian Cancer
- first-line therapy in combination with cisplatin in patients with advanced ovarian cancer or a residual tumor (more than 1 cm) after surgery;
- second-line therapy in patients with metastatic ovarian cancer in the event that standard therapy with platinum drugs is ineffective.
Mammary cancer
- adjuvant therapy in patients with lymph node metastases after therapy with anthracyclines and cyclophosphamide (AC). Adjuvant therapy with paclitaxel should be considered as an alternative to prolonged therapy with AC;
- first-line treatment of metastatic breast cancer after relapse of the disease within 6 months after initiation of adjuvant therapy with the inclusion of anthracycline-based drugs, in the absence of contraindications for their use;
- first-line treatment of locally advanced or metastatic breast cancer in combination with anthracycline-based drugs in the absence of contraindications for their use, or with trastuzumab in patients with immunohistochemically confirmed 2+ or 3+ levels of expression of type 2 receptors of human epidermal growth factor (HER- 2) in the presence of contraindications to anthracyclines;
- second-line therapy (monotherapy) of metastatic breast cancer in case of ineffectiveness of standard therapy including anthracycline-based drugs in the absence of contraindications for their use.
Non-small cell lung cancer
- first-line treatment of advanced non-small cell lung cancer in combination with cisplatin in the event that surgical treatment and / or radiation therapy is not possible.
Kaposi's sarcoma in patients with AIDS
- second line therapy of progressive Kaposi's sarcoma in AIDS patients after ineffective therapy with liposomal anthracyclines.
DOSING MODE
When choosing the regimen and doses in each individual case, one should be guided by the literature data.
To prevent severe hypersensitivity reactions, all patients should undergo premedication with GCS, antihistamines and antagonists of histamine H 1 and H 2 receptors.The recommended mode of premedication is presented in Table 1.
Table 1. Recommended mode of premedication
Drug preparation Dose (mg) Method of administration
Dexamethasone 20 * Inside approximately 12 hours and 6 hours before the administration of the drug Paclitaxel-Teva or IV for 30-60 minutes before the administration of the drug Paclitaxel-Teva
Diphenhydramine ** 50 V / in 30-60 minutes before the administration of the drug Paclitaxel-Teva
Cimetidine or ranitidine 300 50 IV for 30-60 minutes before the administration of Paclitaxel-Teva
* 8-20 mg for patients with Kaposi's sarcoma;
** or its equivalent, for example, chlorpheniramine 10 mg IV.
Ovarian Cancer
Therapy of the first line
At a dose of 175 mg / m 2 as a 3-hour IV infusion followed by cisplatin every 3 weeks or at a dose of 135 mg / m 2 as a 24-hour IV infusion followed by cisplatin every 3 weeks.
Therapy of the second line (monotherapy)
At a dose of 175 mg / m 2 as a 3-hour IV infusion once every 3 weeks.
Mammary cancer
Adjuvant therapy
After a standard combination treatment, 4 courses of therapy with Paclitaxel-Teva are given at a dose of 175 mg / m 2 as a 3-hour IV infusion every 3 weeks.
Therapy of the first line
Monotherapy: at a dose of 175 mg / m 2 as a 3-hour IV infusion every 3 weeks.
In combination with doxorubicin: 24 hours after the administration of doxorubicin - at a dose of 220 mg / m 2 as a 3-hour IV infusion every 3 weeks.
In combination with trastuzumab: the day after the administration of the first dose of trastuzumab - at a dose of 175 mg / m 2 as a 3-hour IV infusion every 3 weeks;with good tolerability of trastuzumab - immediately after the introduction of subsequent doses of trastuzumab.
Therapy of the second line
At a dose of 175 mg / m 2 in the form of a 3-hour IV infusion every 3 weeks.
Non-small cell lung cancer
At a dose of 175 mg / m 2 as a 3-hour IV infusion followed by cisplatin every 3 weeks or at a dose of 135 mg / m 2 as a 24-hour IV infusion followed by cisplatin every 3 weeks.
Kaposi's sarcoma in patients with AIDS
Therapy of the second line
The recommended dose is 135 mg / m 2 as a 3-hour infusion every 3 weeks or 100 mg / m 2 as a 3-hour intravenous infusion every 2 weeks.
Depending on the severity of immunosuppression in patients with AIDS, the administration of the drug Paclitaxel-Teva is recommended only if the absolute number of neutrophils (AKN) is not less than 1000 / ОјL and the platelet count is at least 75,000 / Ојl. Patients with severe neutropenia (AKN less than 500 / ОјL for 7 days or more), or with severe peripheral neuropathy, or with mucositis (grade III or higher) in the following courses are recommended to reduce the dose by 25% to a dose of 75 mg / m 2 . It is necessary to consider the possibility of mobilization of peripheral stem cells by the introduction of granulocyte colony-stimulating factor.
Dosing in the treatment of breast cancer, ovarian cancer, non-small cell lung cancer
The administration of Paclitaxel-Teva should not be repeated until the ACN reaches at least 1500 / ОјL and the platelet count is at least 100,000 / Ојl. Patients who have had severe neutropenia (AKN less than 500 / ОјL for 7 days or longer) or severe peripheral neuropathy after the administration of Paclitaxel-Teva, the dose of Paclitaxel-Teva should be reduced by 20% in the treatment of non-small cell lung cancer and in the treatment of the first line of ovarian cancer or by 25% in the treatment of breast cancer and ovarian cancer . In patients with mucositis (grade II or higher), a dose reduction of 25% is recommended.
Patients with impaired hepatic function
Patients with hepatic insufficiency and associated increased risk of toxicity (in particular, myelosuppression of III-IV degree) are recommended dose adjustment.
The condition of patients must be carefully monitored. Recommended doses are presented in Table 2.
Table 2. Recommended doses for patients with impaired liver function.
Degree of kidney failure
Activity of "hepatic" enzymes Serum bilirubin concentration (Ојmol / L) Dose * of preparation Paclitaxel-Teva mg / m 2
24 hour infusion
<2? VGN and? 26 135
2- <10? VGN and? 26 100
<10? VGN and 28-129 50
?? VGN or> 129 Not recommended
3 hour infusion
<10? VGN and? 22? VGN 175
<10? VGN and 22-35? VGN 135
<10? VGN and 35-86? VGN 90
? 10? VGN or> 86? VGN Not recommended
* Recommended doses for the first course of therapy; dose adjustment in subsequent courses should be based on the individual tolerability of the drug.
Patients with impaired renal function
There is insufficient data on the manifestation of the toxic effect of the drug Paclitaxel-Teva in patients with impaired renal function. Correction of the dose is not required.
Rules for the preparation of a solution for infusion
The infusion solution is prepared immediately before administration, diluting the concentrate with 0.9% sodium chloride solution, or 5% dextrose solution, or 5% dextrose solution in a 0.9% solution of sodium chloride for injection, or 5% dextrose solution in Ringer's solution to a final concentration of 0.3 to 1.2 mg / ml. The prepared solutions may be opalescent due to the presence of composition of the dosage form of the carrier base, and after filtration, the opalescence of the solution is maintained.
When preparing, storing and administering Paclitaxel-Teva, you should use equipment that does not contain plasticized PVC parts. The plasticizer diethylhexyl phthalate (DEHP) contained in plasticized PVC can be released by the action of macrogolglycerylriciniloleate, which is an auxiliary component of the preparation.
Paclitaxel-Teva should be injected through a system with a built-in membrane filter (pore size not more than 0.22 microns).
If unopened vials are placed in the refrigerator, a precipitate may form which dissolves again with little stirring (or without stirring) when room temperature is reached. The quality of the product does not deteriorate. If the solution remains cloudy, or if there is an insoluble deposit, the vial should be destroyed.
SIDE EFFECT
The frequency and severity of adverse reactions with monotherapy with paclitaxel are generally similar in patients with various solid tumors (ovarian cancer, breast cancer, non-small cell lung cancer). The dependence of the toxicity of paclitaxel on the age of patients was not revealed.
The incidence of side effects is classified according to WHO recommendations: very often (at least 10%), often (at least 1% but less than 10%), infrequently (not less than 0.1% but less than 1%), rarely (at least 0.01% , but less than 0.1%), very rarely, including isolated cases (less than 0.01%).
Infectious diseases: very often - infections (mainly the urinary tract and upper respiratory tract), including reports of death; infrequently - septic shock; rarely - sepsis, peritonitis, pneumonia.
With the hemopoietic system: very often - myelosuppression, neutropenia, anemia, thrombocytopenia, leukopenia, bleeding; rarely - febrile neutropenia; very rarely - acute myeloblastic leukemia, myelodysplastic syndrome. The inhibition of bone marrow function, mainly of the granulocyte germ, was the main toxic effect limiting the dose of the drug. The maximum decrease in ACN is usually observed on day 8-11, normalization occurs on day 22.
From the immune system: very often - minor reactions of hypersensitivity (mainly skin rash); infrequent reactions of hypersensitivity requiring medication (lowering blood pressure), angioedema, respiratory distress syndrome, generalized urticaria, chills, back pain, chest pain, tachycardia, pain in the extremities, increased sweating and increased blood pressure); rarely - anaphylactic reactions, confusion; very rarely - anaphylactic shock.
From the side of metabolism : unknown frequency - tumor lysis syndrome.
From the side of the nervous system: very often - neurotoxicity, mainly peripheral polyneuropathy; rarely - peripheral motor neuropathy (leading to distal weakness);very rarely - convulsive attacks such as grand mal, vegetative neuropathy, leading to paralytic obstruction of the intestine and orthostatic hypotension, encephalopathy, convulsions, dizziness, ataxia, headache.
From the side of the organ of vision: very rarely - optic nerve damage and / or visual impairment ("scintillating scotoma"), especially in patients who received doses higher than those recommended; unknown frequency - macular edema, photopsy, "floating" turbidity of the vitreous.
From the side of the hearing organ and labyrinthine disturbances: very rarely - hearing loss, tinnitus, vertigo.
From the cardiovascular system: very often - a decrease in blood pressure, "hot flashes"; often bradycardia; infrequently, myocardial infarction, AV blockade, syncope, cardiomyopathy, asymptomatic ventricular tachycardia, incl. with bigemia, thrombosis of venous vessels, increased blood pressure, thrombophlebitis; rarely - heart failure; very rarely - ventricular fibrillation, supraventricular tachycardia, shock; unknown frequency - phlebitis.
On the part of the respiratory system : rarely - respiratory failure, pulmonary embolism, lung fibrosis, interstitial pneumonia, dyspnea, pleural effusion; very rarely - cough.
On the part of the digestive system: very often - diarrhea, vomiting, nausea, inflammation of the oral mucosa; rarely - intestinal obstruction, intestinal perforation, ischemic colitis, pancreatitis; very rarely - anorexia, thrombosis of the mesenterial arteries of the mesentery, pseudomembranous colitis, neutropenic colitis, ascites, esophagitis, constipation, liver necrosis, hepatic encephalopathy with fatal outcome.
From the skin and subcutaneous tissues: very often - alopecia; infrequently - reversible changes in skin and nails; rarely - skin itching, skin rash, erythema; very rarely - Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (it is recommended to apply sunscreen on hands and feet); unknown frequency - scleroderma.
From the osteomuscular system and connective tissue: very often - arthralgia, myalgia; unknown frequency - systemic lupus erythematosus.
Local reactions: often - reactions at the injection site (edema, pain, erythema and densification, in some cases - hemorrhage, which can cause inflammation of the subcutaneous tissue, skin fibrosis and skin necrosis).
Laboratory data: often marked increase in ACT activity, AF; infrequent increase in bilirubin concentration; rarely - increasing the concentration of creatinine.
Other: rarely - fever, dehydration, asthenia, peripheral edema, general malaise, fever.
CONTRAINDICATIONS
- hypersensitivity to paclitaxel or to other components of the drug, incl. to polyoxyethylated castor oil (macrogol glycerylriciniloleate);
- initial ACN less than 1500 / ОјL in patients with solid tumors;
- initial (or registered during treatment) AKN less than 1000 / ОјL in patients with Kaposi's sarcoma;
- concomitant severe uncontrolled infections in patients with Kaposi's sarcoma;
severe liver dysfunction;
- Pregnancy;
- the period of lactation (breastfeeding);
- Children's age (safety and efficacy not established).
With caution: oppression of bone marrow hematopoiesis, thrombocytopenia (less than 100 000 / Ојl), mild and moderate liver dysfunction, acute infectious diseases (including herpes zoster, chicken pox, herpes), severe course of ischemic heart disease, myocardial infarction (in anamnesis ), arrhythmias.
PREGNANCY AND LACTATION
The drug is contraindicated in pregnancy and during breastfeeding.
Men and women of reproductive age should be treated with effective methods of contraception during treatment with Paclitaxel-Teva and at least 6 months after the end of therapy.
Men should be advised to carry out cryopreservation of sperm before starting treatment with the drug Paclitaxel-Teva because of the possible development of infertility.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution: liver failure.
APPLICATION FOR CHILDREN
Contraindication: child age (safety and efficacy not established).
SPECIAL INSTRUCTIONS
Treatment with the drug Paclitaxel-Teva is carried out under the supervision of a doctor who has experience with antitumor chemotherapeutic drugs. Given the possibility of extravasation, it is necessary to control the administration of the drug Paclitaxel-Teva.
It should be taken into account that in connection with the possibility of developing serious reactions of hypersensitivity, appropriate precautions must be taken in advance. Serious hypersensitivity reactions, accompanied by shortness of breath, arterial hypotension, requiring therapeutic intervention, generalized urticaria, were observed in less than 1% of patients who received the drug Paclitaxel-Teva after adequate premedication. These reactions are probably histamine-mediated. In case of severe hypersensitivity reactions, the infusion of Paclitaxel-Teva should be stopped immediately and symptomatic treatment started. Re-administer the drug Paclitaxel-Teva to such patients should not.
If Paclitaxel Teva-drug is used in combination with cisplatin, administered drug must first Paclitaxel-Teva, and then cisplatin.
Inhibition of bone marrow function (primarily neutropenia) is the main toxic effect of limiting the dose-Paclitaxel Teva. During treatment should regularly monitor the blood count.
Patients with hepatic impairment are most at risk of toxic effects of the drug Paclitaxel-Teva, which may occur myelosuppression grade 3-4. There is no evidence that patients with moderate hepatic impairment may increase the toxic effects at a 3-hour infusion Paclitaxel-Teva. When administered over prolonged drug Paclitaxel-Teva degree of myelosuppression is increased in patients with moderate to severe hepatic insufficiency. Insufficient data to recommend a change in the dose-Paclitaxel Teva in patients with mild to moderate hepatic impairment. There are no data on the use of the drug-Paclitaxel Teva in patients with severe baseline cholestasis. In patients with severe hepatic impairment, the use of Paclitaxel Teva drug is not recommended.
When monotherapy Paclitaxel Teva-impaired heart conduction is rare. In cases of severe disturbances AV-conduction after repeated administration necessary to carry out the appropriate therapy or discontinuous cardiac monitoring. Reduction and increase in blood pressure, bradycardia, recorded during a cardiac monitoring is usually not accompanied by subjective symptoms and require no treatment. The most common change in vital signs, cardiac activity is observed within the first hour of infusion-Paclitaxel Teva. Severe cardiac abnormalities are more common in patients with nemelkokletonym lung cancer than ovarian cancer and breast cancer. In patients with Kaposi's sarcoma have been no cases of heart failure.
Before the metastatic breast cancer first-line treatment combination-drug Paclitaxel Teva with doxorubicin or trastuzumab cardiac performance of the patient must be carefully examined (medical history, clinical examination, electrocardiography, echocardiography, isotopic mnogovhodnaya arteriography). During treatment, these combinations require thorough cardiac monitoring (e.g., every 3 months) in order to be able to identify patients with a progressive disorder of cardiac function and in time to modify the cumulative dose (mg / m 2) Anthracyclines. By reducing the contractile function of the myocardium, even if asymptomatic, the physician should carefully evaluate the ratio of the expected benefits of the duration of chemotherapy and possible risk of deterioration of cardiac function, including the risk of myocardial damage is not reversible. In case of continuing chemotherapy cardiac monitoring should be conducted more frequently (e.g., 1-2 cycles). Further information can be found in the instructions for the medical use of drugs doxorubicin and trastuzumab.
Despite the fact that when using the drug Paclitaxel Teva, symptoms of peripheral neuropathy occurs frequently, severe their symptoms are rarely observed.
Drug Paclitaxel-Teva in combination with radiation therapy, regardless of the history of application of this regimen may contribute interstitial pneumonitis.
Rare cases of pseudomembranous colitis in patients who simultaneously with the drug Paclitaxel-Teva did not use antibiotics, it is necessary to differentiate the cases of severe or persistent diarrhea, which may occur during or shortly after treatment with paclitaxel-Teva.
Because Paclitaxel Teva drug-containing ethanol (396 mg / ml), it is necessary to consider the possibility of adverse reactions in the CNS.
Paclitaxel-Teva is a cytotoxic substance, which during operation care must be taken to use gloves and avoid contact with the skin or mucous membranes, which in such cases should be carefully washed with soap and water, or (eyes) with plenty of water.
After dilution of the concentrate physico-chemical stability of the drug Paclitaxel-Teva is maintained for 96 hours at a temperature less than 25 В° C. After reconstitution, the solution should not be frozen.
Impact on the ability to drive vehicles and manage mechanisms
In the period of treatment with Paclitaxel-Teva patients should be careful when driving vehicles and occupation of other potentially hazardous activities that require high concentration and psychomotor speed reactions, in connection with the possible development of vertigo.
OVERDOSE
Symptoms: inhibition of bone marrow, peripheral neuropathy, mucositis.
Treatment: symptomatic therapy. Antidote to paclitaxel is not known.
DRUG INTERACTION
In the first-line therapy of ovarian cancer paclitaxel should be applied before the cisplatin. When paclitaxel is used before cisplatin, without the risk profile corresponding to paclitaxel with paclitaxel monotherapy. If paclitaxel is applied after cisplatin, patients observed more severe myelosuppression, and 25% paclitaxel clearance is reduced. In patients treated with paclitaxel / cisplatin, the risk of kidney failure is higher than with cisplatin monotherapy in the treatment of cancer of the pelvic organs in women.
In the treatment of breast cancer paclitaxel / paclitaxel infusion doxorubicin should be carried out 24 hours after the administration of doxorubicin. In the case of the earlier administration of paclitaxel can be reduced excretion of doxorubicin and its active metabolites.
Metabolism of paclitaxel is catalyzed, especially CYP2C8 and CYP3A4 isozymes of cytochrome P450. The simultaneous use of potent inhibitors of isoenzyme CYP3A4, such as ketoconazole, does not prevent the removal of paclitaxel in patients, however there is no need to carry out dose correction.
Other data on potential drug interactions between paclitaxel and other CYP3A4 isoenzyme inhibitors are limited. Therefore, caution should be exercised when applying paclitaxel in conjunction with known inhibitors isoenzymes CYP2C8 and CYP3A4 (e.g., erythromycin, fluoxetine, gemfibrozil) or inducers isoenzymes CYP2C8 and CYP3A4 (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine).
Concomitant use of cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect the binding of paclitaxel to plasma proteins.
Systemic clearance of paclitaxel was significantly lower with nelfinavir and ritonavir and is not changed when applied with indinavir. On reacting paclitaxel with other protease inhibitors is insufficient information. Therefore, caution should be exercised when applying paclitaxel in patients taking protease inhibitors.
Polyoxyethylated castor oil, which is part of paclitaxel can cause extraction of DEHP plasticized PVC containers, the degree of leaching of DEHP increases with increasing solution concentration and with time.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children, protected from light, at a temperature of no higher than 25 В° C. Shelf life - 2 years.
